Role of Kinase Fyn in Levodopa-induced Dyskinesia

Target Validation, 2014

Study Rationale:Levodopa frequently induces dyskinesia, an abnormal involuntary movement. In our laboratory we study how and where the prolonged use of levodopa modifies the brain of pre-clinical models of PD. We have analyzed how certain genes are increased by the effects of levodopa in a part of the brain called the “corpus striatum” (an anatomical structure involved in PD). Our results led us to propose that a molecule called Fyn could be responsible in part for the development of dyskinesia. Fyn is a substance present inside nerve cells and helps in communicating signals or chemical instructions between different cellular components.

Hypothesis:We believe that changes in the mechanism that exchanges information between nerve cells is involved in the cause of dyskinesia. Our idea is that Fyn is modified by the treatment with levodopa and if we can find ways to control these modifications, we could reduce dyskinesia.

Study Design:We will develop a model of levodopa-induced dyskinesia to analyze the effect of gene silencing techniques (block the capacity of genes to generate molecules) on these abnormal behaviors. We will use both Fyn knock-out (KO) models as well as viral vectors (modified viruses that introduce genetic commands into the nerve cell), that will allow us to silence gene expression in a time controlled manner and in precise and discrete areas of the brain. We expect that Fyn KO models will show a reduction in the expression of dyskinesia. On the other hand, in models that have a preserved capacity to produce Fyn and in which we will induce the development of dyskinesia, we will attempt to stop the production of Fyn. We expect that this approach will result in a reduction of levodopa-induced dyskinesia without interfering with levodopa’s antiparkinson efficacy.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Our experiments may set the ground for the identification of potential targets for genetic or pharmacological intervention through modifications of the activity of Fyn.

Next Steps for Development:If our results give conclusive evidence that Fyn and other substances interacting with this molecule participate in the generation of dyskinesias, we will be in a position to follow-up with a search for drugs capable of interfering with Fyn and related molecules, as well as the development of genetic and molecular therapeutic approaches.